Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo

TGF-beta plays a critical role in maintaining immune cells in a resting state by inhibiting cell activation and proliferation. Resting HIV-1 target cells represent the main cellular reservoir after long-term antiretroviral therapy (ART). We hypothesized that releasing cells from TGF-beta-driven signaling would promote latency reversal. To test our hypothesis, we compared HIV-1 latency models with and without TGF-beta and a TGF-beta type 1 receptor inhibitor, galunisertib. We tested the effect of galunisertib in SIV-infected, ART-treated macaques by monitoring SIV-env expression via PET/CT using the 64Cu-DOTA-F(ab ')2 p7D3 probe, along with plasma and tissue viral loads (VLs). Exogenous TGF-beta reduced HIV-1 reactivation in U1 and ACH-2 models. Galunisertib increased HIV-1 latency reversal ex vivo and in PBMCs from HIV-1-infected, ART-treated, aviremic donors. In vivo, oral galunisertib promoted increased total standardized uptake values in PET/CT images in gut and lymph nodes of 5 out of 7 aviremic, long-term ART-treated, SIV-infected macaques. This increase correlated with an increase in SIV RNA in the gut. Two of the 7 animals also exhibited increases in plasma VLs. Higher anti-SIV T cell responses and antibody titers were detected after galunisertib treatment. In summary, our data suggest that blocking TGF-beta signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses.

Automated summary

This study found that blocking TGF-beta signaling can promote HIV-1 latency reversal and enhance anti-SIV immune response, which was verified through experiments.